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Oral presentation

After the breakthrough in the treatment of rheumatoid arthritis and numerous related
disorders with biological therapies targeting TNFa at the Kennedy Institute in London

Millions of patients have tremendously benefitted. However, we cannot cure these diseases
yet and have to search for additional therapeutic targets.

Since it was shown that synovial fibroblasts (SF) are not only effector cells responding
to inflammatory stimuli, but appear endogenously activated and potentially involved
into spreading the disease [1], we searched for the epigenetic modifications leading to the activated phenotype
of these cells.

Epigenetics in its scientific definition "is the study of all heritable and potentially
reversible changes in genome function that do not alter the nucleotide sequence within
the DNA", but might be considered in simpler terms as the regulation of gene expression.

Epigenetic modifications include:

Acetylation,

Methylation,

Phosphorylation,

Sumoylation,

miRs or microRNAs.

Our laboratory is studying these processes and we have found that RASF reside in a
hyperacetylated synovial tissue and appear hypomethylated [2]. Hypomethylation leads to the activated phenotype of RASF which is characterized
by the production of matrix-degrading enzymes and of potent chemokines induced by
Toll-like receptor signalling. Current strategies are designed to methylate these
cells to deactivate and "normalise" them again.

miRs are about 20 nucleotide long smallRNAs acting to destroy specific mRNA.

In the race to identify specific miRs as novel targets we have identified for example,
that interleukin-6 modulates the expression of the Bone Morphogenic Protein Receptor
Type II through a novel STAT3microRNA cluster 17/92 pathway, which helps to explain
the loss of the BMPR2 in the vascular cells in pulmonary hypertension [3]. Moreover, miR-203 is regulating the production of IL-6 [4].